title: Carbon ion beams induce hepatoma cell death by NADPH oxidase-mediated mitochondrial damage.
abstract: Mitochondria are a major source of reactive oxygen species (ROS) and are also the target of cellular ROS. ROS damage to mitochondria leads to dysfunction that further enhances the production of mitochondrial ROS. This feed-forward vicious cycle between mitochondria and ROS induces cell death. Within a few minutes of radiation exposure, NADPH oxidase is activated to elevate the ROS level. Activated NADPH oxidase might induce the feed-forward cycle of mitochondria and this is a possible mechanism for cancer cell death induced by heavy ion irradiation. We found that after 4 Gy of (12) C(6+) ion radiation of HepG2 cells, the NADPH oxidase membrane subunit gp91(phox) was not involved in enzyme activation through increased expression; however, the subunit p47(phox) was involved in activation by being translocated to the membrane. (12) C(6+) ion radiation clearly decreased the ΔΨm of HepG2 cells, increasing mitochondrial DNA damage and inducing cell death. Pretreatment with apocynin (APO, an NADPH oxidase inhibitor) effectively prevented the ΔΨm decrease, mitochondrial DNA damage, and cell death induced by radiation. However, these protective effects were not observed with APO treatment after irradiation exposure. These data demonstrated that NADPH oxidase activation was an initiator in mitochondrial damage. Once mitochondria entered the feed-forward cycle, cell fate was no longer controlled by NADPH oxidase. Only antioxidants that targeted mitochondria such as MitoQ could break the cycle and release cells from death.
authors.affiliation: Department of Heavy Ion Radiation Medicine, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, P.R. China; Key Laboratory of Heavy Ion Radiation Medicine of Chinese Academy of Sciences, Lanzhou, P.R. China; Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province, Lanzhou, P.R. China; Graduate University of Chinese Academy of Sciences, Beijing, P.R. China.
authors.forename: Chao
authors.initials: C
authors.lastname: Sun
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Hongyan
authors.initials: H
authors.lastname: Li
authors.forename: Cuixia
authors.initials: C
authors.lastname: Di
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Wu
authors.forename: Lu
authors.initials: L
authors.lastname: Gan
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D004789:Enzyme Activation; D063193:Heavy Ion Radiotherapy / Q000009:adverse effects*; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D008562:Membrane Glycoproteins / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects / Q000528:radiation effects; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000008:administration & dosage; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000528:radiation effects / Q000633:toxicity*; D014451:Ubiquinone / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000975:Antioxidants; D008562:Membrane Glycoproteins; D009943:Organophosphorus Compounds; D017382:Reactive Oxygen Species; C553975:p37 protein, human; D014451:Ubiquinone; C429014:mitoquinone; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases